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Palladium is a powerful catalyst used in catalytic
converters to transform harmful fumes from car exhausts into less toxic chemicals.
It has also played a prominent role in the oil industry for decades and is
broadly used in the industry-scale production of various drugs by Pharma and in
most organic chemistry labs around the world. As chemists, we have learned to
be cautious and treat this and other transition metal catalysts as hazards. However,
in an unusual turn of direction unfolded in recent years, researchers have shown
that palladium is harmless to cells and animals in amounts that serve to
catalyse non-natural chemical processes. This has been applied, for example, to
activate chemically-blocked enzymes within cells or to manufacture anticancer
agents inside tumours. Despite remarkable progress on this new use of palladium,
the challenge of delivering this metal to specific cells, organs or tissues remains
a major barrier to unleash its catalytic power in the clinic.

Exosomes are small lipid vesicles secreted by most eukaryotic
cells that can be taken up by recipient cells at short and long distances. The intercellular
trafficking of exosomes provides an effective communication framework to
exchange biomolecules and regulate physiological functions between parented
cells, including cancer cells. This selective transport system is exploited by some
viruses to spread and infect neighbouring and distant cells, and has inspired
researchers to investigate their use to shuttle therapeutics into specific cell
types. Now, in a collaboration between the Universidad de Zaragoza (led by Prof
Jesús Santamaría) and the University of Edinburgh (Innovative Therapeutics Lab),
it is shown that this communication system can be hijacked to deliver active
palladium catalysts and perform abiotic chemistries into selected cancer cells
(see Figure 1).

Figure 1: Preparation and use of palladium-loaded exosomes
as tumour-targeting bioorthogonal nanoreactors.

Using a mild two-step method involving treatment of cancer-derived exosomes with a Pd (II) salt followed by reduction under a CO atmosphere at low temperature, we have developed a first-in-class bio-artificial vesicle that contains palladium nanosheets of approx. 2 nm in size (see Figure 2) and retains its inherent preferential ability to enter progenitor cells.

By separately harvesting exosomes from lung cancer or glioma
cells and loading them with palladium, the functional capabilities of these multitasking
devices have been proved with the cell-specific synthesis of the anticancer drug
panobinostat in their respective cell of origin. Even if this novel approach is
yet to be tested in more clinically-relevant models, our proof-of-concept study
supports the potential use of exosomes as Trojan horses for the targeted
delivery of metal catalysts to make bioactive agents or sensors not only at the
primary tumour but also in metastatic cells. Could this be the birth of a new
targeted therapy modality ―tentatively named exosome-directed catalyst
prodrug therapy―?

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